This invention relates generally to drug development and, more specifically, to designing compounds that modulate inosine monophosphate dehydrogenase.
The enzyme inosine monophosphate dehydrogenase (IMPDH) is responsible for the rate-limiting step in guanine nucleotide biosynthesis. Because it is up-regulated in rapidly proliferating cells, human type II IMPDH is actively targeted for immunosuppressive, anticancer, and antiviral chemotherapy. The enzyme employs a random-in ordered-out kinetic mechanism where substrate or cofactor can bind first but product is only released after the cofactor leaves. Due to structural and kinetic differences between mammalian and microbial enzymes, most drugs that are successful in the inhibition of mammalian IMPDH are far less effective against the microbial forms of the enzyme. However, with greater knowledge of the structural mechanism of the microbial enzymes, more effective and selective inhibitors of microbial IMPDH can be developed for use as anti-microbial drugs.
Thus, there exists a need for identifying and designing compounds that modulate IMPDH activity. The present invention satisfies this need and provides related advantages as well.